PROJECT SUMMARY Kidney transplantation (KT) is a growing treatment for older adults with end-stage renal disease (ESRD). Even after careful pre-operative cognitive screening, post-KT incidence of Alzheimer's disease and related dementias (ADRD) is high. Presence of diagnosed ADRD increases the risk of graft loss, and more than doubles post-KT mortality risk; thus, understanding post-KT ADRD is of great clinical significance. Prior studies have suggested that ADRD may be a down-stream corollary of post-operative delirium, an acute decline and fluctuation in behaviors related to attentional capacity that is often preventable in older surgical patients. In fact, our preliminary data from medical claims suggested that older KT recipients with post-KT delirium were 5-fold more likely to be diagnosed with downstream ADRD. Therefore, we assessed 72 KT recipients initially free of cognitive impairment for delirium using the Delirium Rating Scale (DRS-98) and Confusion Assessment Method (CAM), and found that 93% experienced post-KT sub-syndromal delirium symptoms, 64% had moderate delirium, and 15% had severe delirium. The relationship between delirium components (severity, duration, subtypes) and domain-specific cognitive decline is understudied, but could lend insight into neurocognitive underpinnings of the potential delirium-ADRD link. Frailty (low physiologic reserve), comorbidity may be common substrates linking delirium and ADRD, but few underlying mechanisms have been identified. We hypothesize that post-KT delirium, as a marker of cognitive reserve, interfaces with frailty and KT-specific health-related stressors to accelerate cognitive decline and ADRD progression. Older KT recipients are an ideal population to clarify this association; they have a high prevalence of comorbidities and frailty and are screened to be free of dementia prior to KT. We will leverage an ongoing, prospective R01-funded study of frailty and aging in KT recipients. In this K01, we will add novel CAM measures that will be reviewed by a new delirium consensus panel and establish a consensus committee to identify ADRD cases for 500 older (age?50) KT recipients in this cohort. I will work closely with my highly supportive, multidisciplinary advisory team to meet my training goals and accomplish my aims: 1) To assess whether post-KT delirium incidence is associated with steeper global and domain-specific cognitive decline and increased ADRD risk among older KT recipients; 2) To test whether delirium duration, CAM severity, and sub-type are associated with steeper global and domain-specific cognitive decline and increased ADRD risk among older KT recipients; 3) To assess whether post-KT delirium mediates the relationship between pre- and peri-KT factors and ADRD risk. Our findings will help clarify the role of post-operative delirium in cognitive decline and ADRD risk among the highly susceptible surgical population of older KT recipients, and will lend clues into potential underlying mechanisms of the delirium-ADRD relationship.